Combination Pozelimab and Cemdisiran Improves LDH Control in PNH, With Jun Ho Jang, MD, PhD

Patients with paroxysmal nocturnal hemoglobinuria (PNH) who received prior C5 inhibitor therapy exhibited robust control of lactose dehydrogenase (LDH) after transitioning to a combination of pozelimab and cemdisiran with a favorable safety profile compared to standard-of-care ravulizumab therapy, according to results from a phase 3 trial.1

Presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition by Jun Ho Jang, MD, PhD, a professor in the division of hematology-oncology at the Samsung Medical Center, this study highlights a new potential treatment pathway for PNH which may result in complete and durable inhibition of C5.1

“This clinical trial shows the safety data is similar to the other clinical trials,” Jang told HCPLive in an exclusive interview. “But, from an efficacy view, dual inhibition is more effective because our data shows that the LDH level was maintained around 1, but other clinical trials have shown that LDH is maintained around 1.5.”

PNH is an extremely rare disorder, with an incidence of around 1 per million and a prevalence of around 8 per million in the US. The disease is caused by somatic mutations in the X-linked phosphatidylinositol glycan anchor biosynthesis class A gene, which triggers complete or partial deficiency of glycosylphosphatidil-anchored proteins (GPI-APs). This makes PNH erythrocytes sensitive to intravascular hemolysis and thrombosis. Additionally, PNH clones can be found in patients with aplastic anemia, due to GPI-APs escaping immune attack.2

This study was an open-label extension of a previous phase 3, open-label, active-controlled study, which indicated that the combo treatment led to robust control of LDH, with more patients achieving meaningful LDH control versus ravulizumab. The extension is a phase 3, open-label, 2-arm, multicenter study, consisting of a 108-week treatment period followed by a 52-week post-treatment safety follow-up for any patient who discontinued treatment. Patients who had received combo during the parent study continued to receive combo, while those who were assigned to ravulizumab were assigned to combo.1

The primary efficacy endpoint for the extension was percent change in LDH from baseline to week 36. For patients given combo, baseline was defined as the last assessment prior to the first dose of treatment in the extension study. For those who had received ravulizumab in the parent study, baseline was the last assessment prior to the first dose of cemdisiran. Secondary endpoitns included change in CH50, transfusion avoidance, and breakthrough hemolysis events.1

A total of 44 patients were included in the extension, of whom 19 patients on combo and 22 patients switched from ravulizumab received treatment until week 36. Mean baseline LDH was 22.1 U/L for patients staying on combo and 312.4 U/L for patients switched to ravulizumab. At week 36, the mean percent change from baseline was +6.4 for patients staying on combo and -19.7 for those switched to ravulizumab. After the first dose of combo, 21 of 22 patients in each arm maintained adequate control of LDH, defined as ≤1.5x the upper limit of normal. All patients who switched from ravulizumab achieved and maintained CH50 levels of 0 U/mL from baseline to week 24, with a mean change of -15 U/mL from baseline.1

Ultimately, Jang and colleagues determined that combo therapy resulted in robust control of LDH. It was well-tolerated, with a favorable safety profile and no adverse events related to the development of large immune complexes or type III hypersensitivity reactions.1

“Nowadays, we have lots of treatment options for PNH,” Jang said. “But, to select a specific treatment, we need to consider many factors, such as patient aging, morbidity, patient prevalence, and transfusion dependency.”

Editor's Note: Jang reports disclosures with AstraZeneca, Novartis, Samsung Bioepis, Sanofi, Regeneron, Kyowa Kirin, and others.

References

1. Jang JH, Patriquin C, Taneja D, et al. Efficacy and safety of pozelimab plus cemdisiran versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria who received prior C5 therapy. Abstract presented at the 67th American Society of Hematology Annual Meeting. Orlando, FL. December 6-9, 2025.

2. Bravo-Perez C, Guarnera L, Williams ND, Visconte V. Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment. Medicina (Kaunas). 2023;59(9):1612. Published 2023 Sep 6. doi:10.3390/medicina59091612